Type II insulin resistant diabetes mellitus accounts for 90-95% of all diabetes. Changed sedentary life style has contributed towards affliction of the disease to adult population also. The main force driving this increasing incidence is a staggering increase in obesity, the single most important contributor to the pathogenesis of diabetes mellitus. Prolonged disease condition leads to chronic macrovascular complications such as retinopathy and nephropathy. The disease is collectively referred, as metabolic syndrome encompasses type II diabetes and common constellation of closely linked clinical features. Characteristic factors include insulin resistance per se, obesity, hypertension and a common form of dyslipidemia and low high-density lipoprotein cholesterol. Metabolic syndrome is associated with marked increased incidence of coronary, cerebral and peripheral artery disease [Executive summary of the third report of the National Cholesterol Program Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults (2001), J. Am. Med. Asso. 285, 2486-2496.].
The role of peripheral and hepatic insulin resistance in the pathogenesis of diabetes mellitus is undisputed. Insulin resistance can be due to multiple defects in signal transduction such as impaired activation of insulin receptor-tyrosine kinase and reduced activation of insulin-stimulated phosphatidyl inositol-3-hydroxy kinase. The resistance of insulin due to diet-induced obesity [Elchebly, M. et al. (1999), Science, 283, 1544.] has given the critical role of obesity in the development of insulin resistance and other features of the metabolic syndrome. Successful approaches attenuating appetite and/or enhancing energy expenditure will prove of great benefit in preventing and treating type II diabetes. Abnormalities of fatty acid metabolism are increasingly recognized as key components of the pathogenesis of the metabolic syndrome and type II diabetes. A critical player in potentiating the promoting effect of hyperinsulinaemia on hepatic lipid accumulation is the anabolic transcription factor SREBP-1, which upregulates genes such as that for fatty acid synthase [Shimomura, I. et al. (2000), Mol. Cell, 6, 77-86.]. These observations support a unified “lipotoxicity” hypothesis, which states that metabolic syndrome and type II diabetes can be caused by the accumulation of triglycerides and long chain fatty-acyl-CoA in liver and muscle. The third causal factor of metabolic syndrome is oxidative stress. Excess levels of oxygen in the living body can also pose a serious health threat; the so-called oxygen toxicity is brought about by oxygen species such as hydrogen peroxide and oxy radicals and damage living tissue. The active oxygen species are associated with diabetes mellitus and are destructive towards various tissues as occurring in diabetes mellitus. There have been many reports discussing relationships between peroxidation and diseases such as diabetes mellitus, atherosclerosis and myocardial ischemia in terms of radical oxidation. Glucose is oxidized under oxidative stress to highly reactive species, which ultimately reacts with proteins. Glucose, like other alpha hydroxy aldehydes, can enolize and thereby reduce molecular oxygen under physiological conditions, catalyzed by transition metals, yielding alpha keto aldehydes and oxidizing intermediates. These secondary compounds are more reactive than monosaccharides and can react with proteins to form cross-linked Mallard products (Simon P. Wolff et al. (1991); Free Radical Biology and Medicine, 10, 339-352.).
Oxidative stress also modifies lipids. Like glucose, LDL also undergoes oxidative modification to form modified LDL (oxidized LDL). The actual oxidation process is believed to begin with lipid peroxidation, followed by fragmentation to give short chain aldehydes. These aldehydes in turn react with the lysine residues of apo-B, creating a new epitope, which is recognized by the scavenger receptor of macrophages. During this same process, lecithin is converted to lysolecithin, which is a selective chemotactic agent for monocytes. The monocytes enter the subendothelium and undergo a phenotypic change to a macrophage, which avidly take up the oxidized LDL via the scavenger receptor. The uptake of oxidized LDL continues until the macrophage is so engorged with cholesteryl esters that it transforms into a foam cell. Groups of these foam cells constitute a fatty streak, the earliest hallmark of atherosclerosis. By inhibiting the oxidation of LDL, it is hoped that the modification of apo B and the production of chemotactic lysolecithin can be prevented and in turn the atherosclerosis.
At present, therapy for type II diabetes relies mainly on several approaches intended to reduce the hyperglycemia itself: sulphonylureas which increase insulin secretion from pancreatic beta cells; metformin which acts to reduce hepatic glucose production, peroxisome proliferator activated receptor-γ agonists which enhance insulin action and α-glucosidase inhibitors which interfere with gut glucose absorption. These therapies have limited efficacy, limited tolerability and mechanism-based toxicity. Of particular concern is the tendency for most treatments to enhance weight gain. A problem particular to the sulphonylureas is that many patients who respond initially become refractory to treatment overtime.
The increasing prevalence of obesity and its associated comorbidities including type II diabetes and related cardiovascular disorders has stimulated efforts to develop effective new approaches in the treatment of this condition. While most therapeutic approaches involve altering the balance of metabolic energy by reducing energy intake, an alternative approach for the management of obesity is to affect an increase in the rate of energy expenditure. In 1984, compounds of the phenethanolamine class as shown below having thermogenic properties in rodents were first disclosed. Despite their structural similarity to known β1 and β2 adrenoceptor ligands, pharmacological studies indicated that these compounds stimulated a third or ‘atypical’ β-adrenergic receptor (β-AR) that is now described as β3-AR. β3 agonist also increased insulin sensitivity and glucose utilization. Later studies suggested that Tyr 64 Arg β3-AR mutation in the human population plays a role in the development of diabetes mellitus and/or obesity in some individuals possessing this genetic variant [Turner, N. C.; (1996), DDT, 1, 109-116].

A family of transcription factors, known as PPAR-γ plays a crucial role in regulating the storage and catabolism of dietary energy producing materials. There are three PPAR subtypes that are the products of distinct genes and are commonly designated as PPPAR α, γ and δ. PPAR-γ affect body weight through regulation of fatty acid catabolism or energy expenditure. PPAR-γ expressed mainly in adipose tissue plays a pivotal role in regulation of glucose and lipid homeostasis [Willson, T. M. et al. (2000), J. Med. Chem. 43, 527-550].
Troglitazone effectively reduces hyperglycemia, hyperinsulinaemia and hypertriglyceridemia in patients with type II diabetes. The mechanism of pharmacological effects has been shown to involve increased insulin sensitivity effects in skeletal muscle, liver and adipose tissue via the activation of PPAR-γ. As vitamin-E analogue, troglitazone has been demonstrated to be an effective antioxidant; oxidative ring opening and subsequent quinone metabolite formation is believed to be the cause of hepatotoxicity and withdrawal of the drug [Kan He, et al. (2001), Biochemical Pharmacology, 62, 191-198.]. This has led to the modification and resulted in several new molecules.

Grafting of pharmacophores on systems own or very close metabolites may exhibit some times undesired effects. For example first generation of statins though derived from fungal metabolite, is very close analogue of mevalonic acid and therefore function as HMG-CoA reductase inhibitors, block mevalonate production which is involved in cholesterol biosynthesis and hence cholesterol synthesis is inhibited in the cell. Mevalonate is a common precursor for all isoprenoids such as ubiquinones (co enzyme Q 10), the dolichols, and isopentenyl tRNA etc. Therefore, there is a decrease in the synthesis of non-sterol constituents, which may contribute significantly to the side effects, observed with HMG-CoA reductase inhibitors. Similarly in designing of troglitazone, vitamin-E component was used which metabolized to quinonoid intermediate after one electron oxidation. This intermediate is speculated to be the cause of toxicity of troglitazone.
Flavonoids are among the most ubiquitous groups of polyphenolic compounds in foods of plant origin. As integral constituents of the diet, they may exert a wide range of beneficial effects on human health. Flavonoids produce such biological effects through their free radical scavenging antioxidant activities and metal ion chelating abilities. (Cotelle, N. et al, Free Rad. Biol. Med. 1992, 13, 211.). These properties led us to utilize flavones for the synthesis of hybrid molecules as antidiabetic and antidyslipidemic agents by substitution with thermogenic as well as insulin sensitizing pharmacophores.